The transient hypofunction of NMDARs during early postnatal development impairs the CB1R-dependent LTD at the MPP – DG synapse.
If CB1R activation is a necessary step for the induction of MPP LTD, and previous studies have documented altered CB1R functionality in several schizophrenia models (Kaminitz et al., 2014; Szűcs et al., 2016; Osborne et al., 2019), it is plausible that MK-801-treated slices could exhibit altered LTD induction. We tested this prediction by applying LFS (900 pulses at 3 Hz) to the MK-801-treated slices. As shown in Figure 3d, LFS failed to induce LTD at the MPP – DG synapse. Moreover, the stimulation protocol induced potentiation of the MPP fEPSP (fEPSP at 90 min post-LFS in MK-801-treated slices: 139.7 ± 23.12% of baseline, n = 6 slices / 6 animals, Kruskal-Wallis test, Dunn’s post-hoc test, P < 0.05 vs. control; traces and red bars in Figure 3c-d). The synaptic response was sensitive to perfusion of DCG-IV, confirming its presynaptic MPP nature (fEPSP in the presence of DCG-IV: 42.13 ± 8.5% of baseline, Kruskal-Wallis test, Dunn’s post-hoc test, P < 0.05 vs. control; red bars in Figure 3e). Interestingly, the anomalous synaptic potentiation observed in the MK-801-treated slices did not alter the MPP PPF (PPR in control condition: 1.43 ± 0.07; at 90 min post-LFS: 1.5 ± 0.09; Wilcoxon test, P> 0.05; red bars in Figure 3f), suggesting altered functionality of postsynaptic glutamate receptors. The cumulative probability chart in Figure 3g summarizes the magnitude of the MPP LTD observed in control slices (black line), the blockade of LTD in the presence of AM 251 (gray line), and the synaptic response of MK-801-treated slices (red line). These results demonstrate that transient hypofunction of NMDARs during early postnatal development impairs the presynaptic-mediated, CB1R-dependent LTD and triggers aberrant forms of synaptic plasticity in the MPP – DG synapse.